Current methods of treating solid cancers of the brain (i.e. brain tumours) involve one or more of surgery, radiation therapy and chemotherapy. For example, glioblastoma (which is the most common brain cancer in humans) is treated using the Stupp protocol. This involves concomitant radiation/temozolomide-based chemotherapy, followed by adjuvant chemotherapy with temozolomide alone, and is carried out after maximal surgical resection of the tumour. Temozolomide prolongs survival by approximately three months (compared to radiation alone) and the median survival of glioblastoma patients is 15 months. Avastin has been approved for recurrent glioblastomas, but has resulted in little improvement in survival.
Further, even though 50% of glioblastomas are dependent on epidermal growth factor receptor (EGFR) signalling, the clinically available EGFR inhibitors have failed in glioblastoma clinical trials. Some inhibitors did not have sufficient Blood-Brain Barrier (BBB) permeability. Recent studies have also revealed that glioblastomas respond only to type II EGFR inhibitors, whereas type I inhibitors were trialled. Extreme heterogeneity and invasiveness of glioblastomas has also contributed to the failure of molecularly-targeted therapies as effective treatments for brain cancers.
Another class of compounds that has been shown to be effective in a number of non-brain cancers are the tubulin-targeting chemotherapeutics. However, the tubulin inhibitors that are clinically used (e.g. Taxol) are very large molecules that are not able to penetrate the BBB. In addition, Taxol and other tubulin-targeting chemotherapeutics (such as vinblastine and vincristine) have serious side effects (e.g. chemotherapy-induced peripheral neuropathy).
Therefore, there is a need to find new treatments for proliferative diseases, such as cancer, and in particular to find effective treatments for brain cancers.
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